Morphine withdrawal in vitro: potentiation of agonist-dependent polyphosphoinositide breakdown.

Naloxone (10(-5) -10(-9) M) significantly increased the K+ (30 mM)-induced release of [3H[noradrenaline when it was applied to cortical slices taken from morphine-dependent rats but did not change the release of transmitter when applied to slices prepared from non-dependent animals. Therefore, this preparation was considered suitable to study withdrawal-related events and was used to monitor the agonist-induced changes of phospholipase C activity in the withdrawal state. Noradrenaline (1-100 microM) and carbachol (50-500 microM), when applied to cortical slices preincubated with [3H]inositol or with [32P]orthophosphate, dose dependently increased the formation of labeled inositol phosphates or of phosphatidic acid. This confirmed that noradrenaline and carbachol increase phospholipase C activity. This increase was significantly enhanced by naloxone (10(-6) M) when the slices were taken from dependent animals. The results now reported show for the first time in mammalian tissues that opioid withdrawal is associated with changes of phosphoinositide metabolism.